Bupropion hydrochloride, whose chemical name is (±)-1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)aminol]-1-propanone hydrochloride, is a medicine for depression developed by Glaxo Wellcome. Processes for preparing Bupropion hydrochloride have been reported in the literature, such as Chen Ke, et al. described in Chinese Journal of Medicinal Chemistry, Vol. 13, No. 5, 2003 that bupropion hydrochloride can be prepared from 3-chloropropiophenone by chlorination with cupric chloride, amination with t-butylamine, acidification with hydrogen chloride-isopropanol. Even though this method is highly selective and easy to operate, it is costly to treat the waste residue produced by chlorination, which causes environmental problems. This restrains industrial production.
A method reported by Xia Min, et al. for preparation of Bupropion hydrochloride used m-chlorobenzoyl chloride as starting material, after bromination and N-alkylation, bupropion hydrochloride was obtained. N-Bromo succinimide was used for bromination to avoid direct bromination with bromine. The yield of bromination was increased. Polyethylene glycol (PEG) was used as phase-transfer catalyst (PTC) in the N-alkylation reaction to achieve high yield. But this method is not suitable for mass production because of the high cost of the bromination reagent.
As Xu Ziao, et al. described in the Journal of Anhui University, m-chlorobenzoyl chloride was used for raw material. After acylation, Grignard reaction, bromination, and N-alkylation, bupropion hydrochloride was obtained. Although this method is convenient and the total yield is high, the raw material hydrolyzes easily and its quality is not stable, which affects yield and quality of finish product. Therefore, commercial production becomes impractical.
The U.S. Pat. No. 3,819,706 introduced a method for preparation of using m-chlorobenzonitrile as raw material. After Grignard reaction, bromination and amination with t-butylamine, the objective product was obtained. Grignard Reaction requires anhydrous operation, and bromination is hard to control and results in excessive byproducts which are hard to removed in post processing and decrease yield.
The Patent WO2004024674 described that bupropion free base was obtained from m-chloropropiophenone via bromination in the presence of t-butylamine, and then reacted with hydrochloric acid to obtain bupropion hydrochloride. Because t-butylamine is a solvent as well as a reactant in bromination step, this method increases side reactions and cost of production therefore restrains commercial manufacture.
As David L. Musso described (Bioorganic & Medicinal Chemistry Letter, Vol. 7, No. 1. pp. 1-6, 1997), m-chlorobenzoic acid was used as starting material, in the presence of thionyl chloride, ammonium hydroxide and 1,4-dioxane to produce m-chlorobenzonitrile Benzonitrile, then Grignard reaction, bromination and substitution, the target product of bupropion was obtained. This preparation had a long process, complicated operations, high pressure on environment and low yield, also had strict requirements for operations. Therefore, it is not suitable for large scale production.
The methods of prior art for producing bupropion hydrochloride generally have high cost of production, low yields, high requirements for safety, high pressure on environment and long cycle of production.